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LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner

Oncogene volume 41, pages 4042–4054 (2022)Cite this article

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Abstract

LKB1 loss of function is one key oncogenic event in lung cancer. Clinical data suggest that LKB1 loss of function is associated with patients’ smoking status. The responsible ingredients and molecular mechanisms in tobacco for LKB1 loss of function, however, are not defined. In this study, we reported that NNAL, a major metabolite of a tobacco-specific carcinogen NNK, induces LKB1 phosphorylation and its loss of function via the β-AR/PKA signaling pathway in an isomer-dependent manner in human lung cancer cells. NNAL exposure also resulted in enhanced lung cancer cell migration and chemoresistance in an LKB1-dependent manner. A 120-day NNAL exposure in lung cancer cells, mimicking its chronic exposure among smokers, resulted in more prominent LKB1 phosphorylation, cell migration, and chemoresistance even in the absence of NNAL, indicating the long-lasting LKB1 loss of function although such an effect eventually disappeared after NNAL was removed for two months. These observations were confirmed in a lung cancer xenograft model. More importantly, human lung cancer tissues revealed elevated LKB1 phosphorylation in comparison to the paired normal lung tissues. These results suggest that LKB1 loss of function in human lung cancer could be extended to its phosphorylation, which may be mediated by NNAL from tobacco smoke in an isomer-dependent manner via the β-AR/PKA signaling pathway.

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Fig. 1: The potential impact of NNK and NNAL on lung cancer and their physiological relevance.
Fig. 2: The effects of NNAL enantiomers on LKB1 phosphorylation in lung cancer cell lines.
Fig. 3: The effects of NNAL enantiomers on cell migration and cytotoxicity of gemcitabine and cisplatin in lung cancer cell lines.
Fig. 4: The function of LKB1 on malignant phenotypes promoted by NNAL exposure.
Fig. 5: The upstream signaling that governs NNAL-promoted LKB1 phosphorylation and phenotypes.
Fig. 6: LKB1 phosphorylation status and phenotypes in H1299 cells with a 120-day NNAL exposure.
Fig. 7: LKB1 phosphorylation status in tumors of H1299 xenograft models with a 2-week NNK exposure, tumor sensitivity to cisplatin treatment with NNK exposure, and LKB1 phosphorylation status in human lung cancer samples.

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Acknowledgements

The work was partly supported by grants from the National Institute of Health (R01CA193286) to CX, the Harry T. Mangurian Jr. Foundation to CX, College of Pharmacy Frank Duckworth Endowment to CX, University of Florida Health Cancer Center Startup fund to CX, and University of Florida Medicinal Chemistry Mass Spectrometry Support to CX. Y Wu was supported by a scholarship from the National Science Foundation of China. The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication. We also acknowledge the National Cancer Institute for providing PLCO information used in this manuscript. We would like to thank Sreekanth C. Narayanapillai, Santanu Hati, and Pedro Corral for the assistance with sample collection and characterization. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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  1. These authors contributed equally: Tengfei Bian, Yuzhi Wang.

Authors and Affiliations

  1. Department of Medicinal Chemistry, Center for Natural Products, Drug Discovery and Development (CNPD3), University of Florida, Gainesville, FL, 32610, USA

    Tengfei Bian, Yuzhi Wang, Jordy F. Botello, Qi Hu, Yougen Wu & Chengguo Xing

  2. Department of Molecular Medicine, UT Health San Antonio, San Antonio, TX, 78229, USA

    Yunhan Jiang & Lingtao Jin

  3. Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA

    Adriana Zingone & Bríd M. Ryan

  4. Department of Biostatistics, College of Public Health & Health Professions, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Haocheng Ding & Zhiguang Huo

  5. College of Tropical Agriculture and Forestry, Hainan University, 58 Renmin Avenue, Haikou, 570228, China

    Yougen Wu

  6. Department of Pathology, Immunology and Laboratory Medicine, University of Florida, 1345 Center Drive, Gainesville, FL, 32610, USA

    F. Zahra Aly

  7. Department of Health Outcome & Biomedical Informatics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Ramzi G. Salloum

  8. Department of Radiation Oncology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Graham Warren

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Contributions

TB: Designed and performed experiments, analyzed data, wrote the original draft, and reviewed, edited, and revised the manuscript. Y Wang: Designed, performed research, analyzed data, contributed to the original draft, reviewed and edited the manuscript. JFB: Performed the experiments and contributed to the original draft. QH: Performed the experiments. YJ: Performed the experiments. AZ: Provided research reagents. HD: Performed the experiments and analyzed the data. Y Wu: Performed the experiments. FZA: Performed the experiments, analyzed the data, reviewed, and edited the manuscript. RGS: Reviewed and edited the manuscript. GWW: Reviewed and edited the manuscript. ZH: Analyzed the data, reviewed, and edited the manuscript. BR: Provided reagents, reviewed, and edited the manuscript. LJ: Provided reagents, supervised the experiments, reviewed, and edited the manuscript. CX: Conceptualization, designed and supervised the experiments, acquired funding, wrote the original draft, reviewed, edited, and revised the manuscript.

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Correspondence to Chengguo Xing.

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Bian, T., Wang, Y., Botello, J.F. et al. LKB1 phosphorylation and deactivation in lung cancer by NNAL, a metabolite of tobacco-specific carcinogen, in an isomer-dependent manner. Oncogene 41, 4042–4054 (2022). https://doi.org/10.1038/s41388-022-02410-x

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